Use of selective serotonin reuptake inhibitors during pregnancy is associated with neonatal abstinence syndrome and a slightly increased risk of persistent pulmonary hypertension of the newborn, according to results of two recently published studies.
In a case-control study, infants of women who took SSRIs in the second half of pregnancy were five to six times more likely to develop persistent pulmonary hypertension of the newborn (PPHN), with an overall incidence of 1 case for every 100 exposed infants (N. Engl. J. Med. 2006;354:579–87).
In an accompanying editorial, Dr. James L. Mills wrote that “the association is very unlikely to be due to chance … the current study was well designed and carefully executed.” (N. Engl. J. Med. 2006;354:636–8).
In an interview, however, Dr. Gideon Koren of the Motherisk Program in Toronto, who was not involved in either study, cautioned against placing too much significance on the finding. “If you look more carefully at the numbers, it all hinges on two to three cases. These are very small numbers and although this is a large study, [PPHN] is a very rare condition,” he said.
PPHN, which affects 1–2 infants per 1,000 live births, causes significant morbidity and mortality. In the case-control study, Dr. Christina D. Chambers of the University of California, San Diego, and her associates investigated the association between SSRI use and PPHN in 377 women whose infants had PPHN and 836 matched controls.
Within 6 months after delivery, participants were interviewed by nurses unaware of the study hypothesis. Interviewers collected detailed information on demo-graphics, medications taken during pregnancy, and other risk factors.
Fourteen cases of PPHN were noted among women taking SSRIs after the 20th week of gestation, compared with six cases in control infants (adjusted odds ratio 6.1). PPHN was three times more likely with antidepressant use after the 20th week of pregnancy, five times more likely if the antidepressant was an SSRI, and six times more likely after adjustment for confounding variables. No elevation in risk was observed with SSRI use earlier in pregnancy or when non-SSRI antidepressants were used.
The investigators noted that 3% of infants with PPHN died. Dr. Koren said that he spoke with the study investigators, who told him that none of the infants who died were exposed to SSRIs in utero, a fact that is not noted in the published study.
Dr. Koren cautioned that “it would be sad if because of this study, women discontinue SSRIs in late pregnancy, as [depression] can be life threatening for some and a cause of high rates of morbidity. The best predictor of postpartum depression is depression in late pregnancy.”
An unrelated cohort study found that 30% of 60 infants exposed to SSRIs in utero experienced some degree of neonatal abstinence syndrome; none of 60 control infants showed any symptoms of the syndrome. Among the exposed infants, 10 exhibited mild symptoms and 8 had severe symptoms of neonatal abstinence, according to Dr. Rachel Levinson-Castiel of the Schneider Children's Medical Center of Israel in Petah Tiqwa, and her associates (Arch. Pediatr. Adolesc. Med. 2006;160:173–6).
The most common symptoms, measured using the Finnegan score, included tremors (in 37 SSRI-exposed infants vs. 11 control infants), gastrointestinal disturbances (34 vs. 2), sleep disturbance (21 vs. 2), high-pitched cry (18 vs. 0), and hypertonicity or myoclonus (14 vs. 1). Most symptoms peaked within the first 48 hours after delivery, although maximal scores were observed through day 4.
Although the small study size precluded an evaluation of dose effects for most SSRIs, the investigators found a significant association between paroxetine dose and the degree of neonatal abstinence syndrome symptoms. Infants exposed to doses less than 20 mg showed no signs of the syndrome.
While neonatal abstinence syndrome is indeed a result of withdrawal in most infants, Dr. Koren added that in some cases, the symptoms are instead due to a high level of drug in the neonate.
“This is important because if it is a lack of drug [causing the symptoms], you may want to give the baby an SSRI, whereas if it is poisoning you cannot give the drug,” he said.
The study investigators suggested that infants exposed to SSRIs in utero be followed carefully after delivery. “After birth, close monitoring is mandatory. Early discharge of SSRI-exposed infants should be avoided and observation continued until symptoms subside.”